The overall objective of this project is to examine mechanisms by which angiotensin II contributes to vascular dysfunction during hypertension and atherosclerosis. Although the role of angiotensin II in hypertension has been an active area of investigation, the proposed studies will use a novel approach to address the hypothesis that angiotensin II contribute to vascular dysfunction during atherosclerosis. Two new murine models have been produced for these studies- a transgenic mouse that systemically over-expresses human renin and angiotensinogen genes (the systemic model, T+/A+), and a second mouse which over-expresses the same two genes, but expression of angiotensinogen has been restricted to the kidney by the use of a kidney-specific promoter (renal-specific model, R+/K+). A key aspect in the design of the proposed studies relates to the finding that circulating levels of angiotensin II are markedly elevated in the systemic model, but are normal in the renal-specific model. Despite normal levels of plasma angiotensin II in the renal-specific model, the degree of hypertension is similar in the two models. This approach allows the direct examination of the role of human renin and angiotensinogen and circulating angiotensin II in models of hypertension and atherosclerosis. One goal of the studies will be to examine the hypothesis that levels of superoxide are increased and vascular dysfunction is present in hypertensive mice. Because circulating levels of angiotensin II are elevated only in the systemic model, we anticipate that vascular abnormalities will be is greater in the systemic model than in the renal- specific model. A second goal of the studies will be to examine the hypothesis that levels of superoxide and vascular dysfunction during atherosclerosis in the presence of hypertension is greater than during atherosclerosis or hypertension alone. More importantly, proposed experiments will examine the hypothesis that in the presence of hypercholesterolemia, functional abnormalities and the extent of atherosclerosis will be more severe in the systemic model than in the renal-specific model. For studies of atherosclerosis, double transgenic mice will be crossed with apolipoprotein E-deficient mice. A strength of this proposal is the use of novel murine models to characterize systems which contribute to superoxide production and abnormal function in blood vessels. In addition to studies of aorta, a major site of formation of atherosclerotic lesions, coronary and cerebral arteries from mice will also be studied The ability to produce selective alterations in the renin- angiotensin system and then to examine resulting changes in the vascular wall will allow a new approach to examine the role of angiotensin II during hypertension and atherosclerosis.